The Old World hantaviruses, Hantaan virus (HTNV) and Seoul virus (SEOV), are the etiologic agents of hemorrhagic fever with renal syndrome (HFRS), the most common hemorrhagic fever disease in Asia, with case fatality rates up to 15%. Hantaviruses are zoonotic RNA viruses found in insectivore and rodent hosts worldwide. In their respective reservoir hosts, hantaviruses establish asymptomatic, persistent infections. The mechanisms underlying these divergent infection outcomes remain unknown and no therapeutic exists to treat HFRS. We have determined that early antiviral signaling in HTNV infection of murine and human cells requires MAVS, the signaling adapter protein for cytoplasmic pathogen recognition receptors RIG-I and MDA5. Further, we have demonstrated that type I interferon signaling is essential for early control of HTNV replication and tissue dissemination in vivo. Through global transcriptional profiling, we have revealed gene networks responsible for endothelial homeostasis and inflammation that are differentially regulated during SEOV infection between reservoir and human endothelial cells. Predicted network analysis identified differential regulation of the vascular endothelial growth factor (VEGF) receptor signaling pathway, with increased receptor gene expression in human cells coordinate with increased gene expression related to angiogenesis and migration compared to reservoir endothelial cells. We hypothesize that virus-host molecular interactions in Old World hantavirus infections determine innate antiviral responses and drive differential gene expression associated with infection outcome. We will address this hypothesis by: 1) further defining the virus-host interactions that direct antiviral signaling to HTNV infection in human endothelial cells, 2) uncovering the mechanism(s) by which SEOV directs endothelial activation and barrier permeability through differential modulation of VEGF signaling in human and rat endothelial cells. Our investigations will lead to identification of novel targets for therapeutic intervention and innovative strategies for vaccine design for HFRS.